This renewal proposal continues our exploration of the vasa vasorum (the microvessels perfusing the arterial wall) in coronary artery disease. The long-term objective is to clarify the role of solute transport across the arterial wall in the initiation and/or progression of atherosclerosis. The relevance of this knowledge to the mission of NHLBI is that it should provide insight into possible early treatments to arrest or reverse arthrosclerosis and thereby reduce major public health problems resulting from advanced atherosclerosis causing coronary artery stenosis and myocardial infarction. This proposal is designed to test the overall hypothesis that the vasa vasorum can play an important role in the initiation of coronary atherogenesis by virtue of disturbed solute transport within the arterial wall occurring prior to cellular invasion and/or proliferation. So far the question of mere association of changes in vasa vasorum (W) with early atherogenesis has already been answered in the affirmative by our studies. What remains to be determined is to what extent the W actually play a primary or facilitating role in the initiation of the artherosclerotic process or merely respond to that process. Our approach is based primarily on use of micro-CT-based imaging methods including our novel, in-house developed, cryostatic micro-CT method and also by in-vitro characterization of isolated W contractile state. This will involve analysis of coronary arteries of pigs with diet-induced hypercholesterolemia or renal artery stenosis (stent-induced) arterial hypertension, both being risk factors for atherogenesis. AIM I: Explore individual W trees'perfusion territories', function in terms of location, shape, size and washin/washout characteristics. The 3D geometry and solute transport localized function of these territories will form the basis for understanding of lipid accumulation in the arterial wall. AIM II: Explore the role of endothelial permeability in the W and coronary artery using cryostatic micro-CT scans. Use micro embolism to cause acute occlusion of single W near their origin to evaluate the ability of W contiguous in perfusion territories, to compensate for the localized loss of perfusion. AIM III: Following chronic recovery from micro-embolization of some of the W, the relationship between location and size of coronary arterial wall perfusion-voids on the one hand and histologically localized 'lipid1 deposits on the other will be a direct test of the pathological consequences of alterations in solute transport characteristics of W. The specific significance of this proposal is that if W play an important role in the initiation or progression of atherosclerosis, a possible therapeutic benefit that may result from acquiring this new information is that either stimulation (or inhibition;depending on our findings) of vasculogenesis of W could retard the onset and/or severity of atherosclerosis.